The invasive growth of cancer cells into bone tissues often results in severe pain syndromes and may ultimately result in death. Ionizing radiation has been used to achieve a reduction in pain. In particular, external radiation therapy has been applied in cases where bone pain is restricted to focal areas. For disseminated bone metastases, however, a treatment which focuses the radiation dose to bone tissue and particularly to bone metastases is desirable.
Prior to therapy it is necessary to obtain reliable diagnostic information and to this end several approaches have been tried. An approach that has been the subject of a number of patents, for example, U.S. Pat. No. 3,974,268 to Subramanian et al., involves the use of a technetium-99m diphosphonate complex as a skeletal imaging agent. This approach utilizes a diphosphonate as both the bone-seeking agent and the complexing agent for the radionuclide. Such an approach has at least three major disadvantages. First, by involving the bone-seeking agent in the complexation of the metal radionuclide, the ability of the agent to direct, or “target,” the radionuclide to the desired site may be diminished. Second, because diphosphonate salts or chelates are known to form polymers, a preparation of diphosphonates and radionuclides typically includes multiple forms of diphosphonate-radionuclide complexes which have differing charge and uptake properties. Third, the complex formed between a diphosphonate and a radionuclide is not of optimal stability which may necessitate purification of the diphosphonate complex prior to use. Further, even a purified diphosphonate complex may lose the radionuclide during its use.
U.S. Pat. No. 4,853,209, is directed to the use of Sm-153, Gd-159, or Ho-166 complexed with a ligand selected from ethylenediaminetetramethylene-phosphonic acid (EDTMP), diethylenetriaminepentamethylenephosphonic acid (DTPMP), hydroxyethylethylenediaminetrimethylenephosphonic acid (HEEDTMP), nitrilotrimethylenephosphonic acid (NTMP), and tris(2-aminoethyl)aminehexamethylenephosphonic acid (TTHMP), to suppress bone marrow growth.
U.S. Pat. No. 4,882,142, is directed to a method for the suppression of bone marrow and to a composition for use in the method. The method comprises administering a bone marrow suppressing amount of at least one composition comprised of a radionuclide Sm-153, Gd-159, or Ho-166, complexed with 1,4,7,10-tetraazacyclododecanemethylenephosphonic acid as the macrocyclic chelating moiety.
U.S. Pat. No. 5,059,412 is directed to compositions comprising a particle emitting radionuclide complexed with a macrocyclic aminophosphonic acid, wherein the nitrogen and phosphorous are interconnected by an alkylene group.
U.S. Pat. Nos. 5,202,109 and 5,089,249 are directed to conjugates formed from calcified tissue targeting agents and radiolabeled compounds. One conjugate comprises a chelate and a targeting agent that is capable of associating with calcified tissue, wherein the chelate contains at least one nitrogen atom or at least one sulfur atom, or a combination thereof.
In spite of the above disclosures, a continuing need exists for therapeutic and diagnostic agents that are useful for bone marrow suppression, cancer therapy, treating bone pain, and as diagnostic agents. Preferred agents may possess improved stability, improved uptake in bone, or improved retention in bone.